Biophysical prevention of chemotherapy-induced alopecia: Low-intensity ultrasound significantly reduces taxane-induced human hair follicle damage in vivo

Summary: Abstract Body: Chemotherapy-induced alopecia (CIA) remains one of the most distressing adverse effects of cancer therapy. Since there are no pharmacological treatments that reliably protect human hair follicles (HFs) and their epithelial stem cells (eHFSCs) from acute and permanent CIA, we have explored the impact of biophysical disruption of taxane-induced microtubule cross-linking by low-intensity ultrasound (LIUS). While LIUS is known to limittaxane-induced HF and eHFSCs damage ex vivo, it is unknown if this also works in vivo. To probe this, a single dose of paclitaxel (PTX, 20mg/kg) was injected i.p. into SCID/beige mice xenotransplanted with healthy human scalp skin in the presence/absence of LIUS (5min at 45KHz applied 2x in a water bath 6 and 24hr after PTX injection). 30 hours after PTX injection, xenotransplants were cryoembedded for quantitative immunohistomorphometry. This showed that LIUS reduced melanin clumping and ectopic melanin in the anagen hair bulb human scalp HFs, indicating reduced HF toxicity and the % of apoptotic cells was also reduced. Moreover, LIUS significantly reduced DNA damage of eHFSC, i.e., the % of gH2A.x+/K15+ cells, and taxane-induced micronucleation in both the bulge and bulb epithelium. Interestingly, LIUS also significantly increased the protein expression of RARa and RXRg in the bulge and bulb, i.e. key signaling pathways that promote clearance of apoptotic eHFSCs in the bulge of mice. These preclinical data from a novel “humanized” mouse model if CIA provide the first evidence that a simple, widely available biophysical intervention (LIUS) can greatly reduce PTX-induced HF damage in both, highly proliferative hair matrix epithelium and quiescent human eHFSCs in vivo, and strongly support that LIUS promises to limit both acute and permanent taxane-induced CIA. Jeremy Cheret^{1, 2}, Jennifer Gherardini², Tatiana Gomez-Gomez¹, Celina A. Sanchez³, Xiang-Xi Xu³, Tongyu C. Wikramanayake¹, Ralf Paus^{1, 2} 1. Dermatology, University of Miami Miller School of Medicine, Miami, FL, United States. 2. CUTANEON-Skin&Hair Innovations GmbH, Hamburg&Berlin, Germany. 3. Radiation Oncology, University of Miami Miller School of Medicine, Miami, FL, United States. Translational Studies: Preclinical